Panic Disorder (PD) is a common psychiatric illness that afflicts approximately 6 million people annually in the US. Despite considerable research, the neurobiological basis of PD is poorly understood. Most neurobiological models of panic disorder propose two contrasting mechanisms of vulnerability: a) a dysfunction in central metabolically driven alarm system, or b) a supersensitive fear/anxiety system. Consistently, panic disorder patients show an exaggerated lactic acid response to hyperventilation and sodium lactate infusion leading to extreme fear and panic. This reflects a disturbance in the brain pH response and regulation. The interplay between pH regulatory and fear/anxiety systems and their association with panic and fear is important, but not well understood. We have recently cloned a pH sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) from rodent brain amygdala. Presence of a pH sensor in a region regulating fear and anxiety is a novel finding that can provide important leads into the mechanisms underlying panic attacks and associated fear. The overall objective of this R-21 application is to prove the concept that the TDAG8 receptor is relevant for pH-induced amygdalar signaling and panic-associated behavior. Our hypothesis is based on several observations. Firstly, TDAG8 is predominantly expressed in the amygdala, a region implicated in the genesis of fear and panic. Secondly, acidosis (rise in H+) activates TDAG8, leading to an elevation of calcium and pCREB, indicating that TDAG8 signaling may be sensitive to acid-base dys-balance which is observed in PD. Thirdly, brain TDAG8 in the amygdala is regulated by hypoxia which is physiologically relevant to PD. Relevance of TDAG8 in amygdalar signaling as well as panic and fear responses will be tested under two specific aims. Aim 1 To determine whether inhibition of TDAG8 expression impacts acid-evoked signaling in amygdalar neurons and Aim 2 Determine whether TDAG8-deficient mice show resilience to panicogenic stimuli induced panic and fear responses. Relevance: The TDAG8 receptor may provide important leads into acid-base dysregulation and the expression of panic and fear. This association is critical to the pathophysiology of panic and may lead to more specific and effective therapies for PD. Our data will form the basis for a R01 grant to investigate the relevance of TDAG8 in panic disorder. PUBLIC HEALTH RELEVANCE: Panic Disorder (PD) is a common and complex anxiety disorder with a life time prevalence of up to 4%. Specific treatments for PD are not available due to a poor understanding of how panic attacks are induced and translated into chronic fear and anxiety. Disturbance in acid-base balance and abnormality in fear regulation are responsible, however, their exact association is not known. This proposal investigates for the first time, the role of a novel brain pH sensing receptor, the T cell death associated gene 8 (TDAG8) in panic and fear. Our studies will improve the understanding of PD and lead to improved treatments.